Protozoan parasites cause diseases such as malaria, trypanosomiasis, Chagas' disease, leishmaniasis, giardiasis, and amoebiasis. These and other protozoan parasite diseases have historically occurred in tropical and sub-tropical areas where they cause widespread damage to human populations. Although they receive little attention in the Western world, protozoan diseases affect more people worldwide than diseases brought on by any other biological cause (Heyneman, 1988).
The global importance of just one parasitic protozoan disease, malaria, can be appreciated by considering that historically, roughly half of all people who have lived and died have died of malaria. Today, malaria remains the most destructive single infectious disease in the developing world. It is responsible for more human energy loss, more debilitation, more loss of work capacity, and more economic damage than any other human ailment facing the world today (Heyneman, 1988). The World Health organization estimates that 1 to 2 million deaths are caused by malaria each year in Africa alone; most of these are children under the age of five (World Health organization, 1991). In addition, over 300 million people worldwide are believed to be chronically infected, and each year nearly one third of these individuals will suffer acute manifestations of the disease.
Today, the pathologic capacity of protozoa is being increasingly demonstrated in the Western world among the victims of AIDS (Acquired Immunodeficiency Syndrome). AIDS depletes the immune system of affected individuals; this allows opportunistic agents which would be defeated by an active immune system to infect AIDS patients. Several protozoa have emerged as important opportunistic infections in AIDS patients including Cryptosporidium parvum, Entamoeba histolytica, Giardia lamblia, Pneumocystis carinii (which may be a fungal or protozoal pathogen), and Toxoplasmosis gondii.
Despite the prevalence and significance of protozoan infections, therapy for these diseases is generally poor or in need of improvement. Many chemotherapeutic agents used to treat protozoan infections are non-specific cytotoxins that are highly toxic and cause severe side effects in patients. However, these drugs are used because there are no better alternatives. For example, giardiasis and amoebiasis are treated using metronidazole (a nitroimidazole), but the use of this drug is clouded by its mutagenic potential (Campbell, 1986) and its adverse interaction with alcohol. For trypanosomiasis and leishmaniasis standard therapies (suramin, melarsoprol, and pentavalent antimonials) are dangerously toxic, occasionally fatal, and often ineffective (Mebrahtu, 1989; Grogl et al., 1992). Other drugs are becoming ineffective due to emerging resistance. In the case of malaria, effective therapy has previously been provided by chloroquine but its efficacy is now threatened by the rapid emergence of drug resistant strains of Plasmodium falciparum, the causative agent for the most severe, often fatal, form of the disease (Cowman, 1990). Other protozoal infections such as cryptosporidiosis or Chagas' disease have no proven curative agent.
The present invention is directed to new antiparasitic agents and methods of using known compounds as anti-parasitic agents. The invention is also directed to compounds with broad-spectrum anti-microbial activity.